The global magnitude of hepatitis B viral (HBV) infection warrants development of efficient treatment strategies to combat the virus. These treatment protocols will also aid in minimizing the protracted long-term effects of HBV infection namely cirrhosis and hepatocellular carcinoma. The short-term benefits of the currently available treatment protocols are greatly offset by the emergence of the resistant phenotype in the case of Lamivudine therapy and adverse side effects in the case of alpha-interferon. As a consequence of this, the goal of maintaining low viral loads cannot be achieved. The generation of a panel of potent antivirals against HBV would be a valuable addition to existing treatments. Novel combinations of anti-HBV drugs would greatly minimize the chances of development of resistance and provide sustained reduction in viral loads. A number of 2'-fluoro-2',3'-unsaturated D- and L-nucleosides (2'-F-D4N) showed potent anti-HBV activity with no appreciable toxicity in a number of cell lines. These compounds also demonstrated anti-HIV activity in vitro. In the proposed Phase I study, these compounds will be further characterized with respect to their anti-HBV activity in combination treatments, mechanisms of action, mitochondrial toxicity, and efficacy of inhibition of HBV viral polymerase. Cross-resistance of these active nucleosides against the Lamivudine-resistant mutants will be determined. Pharmacokinetics of molecules with antiviral activity and no appreciable cellular and mitochondrial toxicity will be conducted. At the conclusion of the Phase I study, it should be possible to identify one or two best candidate molecules for detailed studies in animal models, preclinical studies and further development. Detailed studies for phase II studies which will include in vivo efficacy and sub chronic toxicology of the compounds. PROPOSED COMMERCIAL APPLICATION: There is an urgent need for therapies for the treatment and management of HBV worldwide. Limited success of the Lamivudine monotherapy and development of clinical resistance to Lamivudine have made the researchers as well as clinicians aware of the fact that alternate modalities of treatment have to be in place to tackle HBV infections successfully. Novel anti-HBV agents, hence, would have a much broader market as new combinations of drugs can be formulated.